tbuckley/cabot-search huggingface dataset:
Abstract P1-10-06: Carcinoma en Cuirasse Secondary to Locally Advanced Breast Carcinoma: a case report
Authors: Chung-Tang Liu, Keri Lanier
Journal: Cancer Research (2023)

Abstract Introduction &amp; Objective This report highlights an unusual presentation of skin metastasis of inflammatory breast cancer that resembles a rare condition called Carcinoma en Cuirasse (CeC). CeC was first described by anatomist Alfred Velpeau in 1838 when he observed how the coalescing nodules and diffuse sclerodermoid induration found on the chest and abdomen in CeC resembled the medieval steel breastplate or a cuirasse. Case Presentation A 62-year-old female presented to the emergency department for evaluation of a palpable left breast mass and concurrent skin lesions for the past 5 months. Based on the erosion of the nipple, chest CT, as well as core needle and skin biopsy, a diagnosis of stage IV (cT4d, cN3, cM1) ER+, PR-, HER2/neu- advanced/inflammatory breast carcinoma was made. The patient underwent a 20-week course of neoadjuvant chemotherapy followed by 25 treatments of neoadjuvant external beam radiotherapy (EBRT) with a total dose of 5000cGy to the left breast and the regional lymph node due to disease progression after 4 cycles of neoadjuvant chemotherapy. She proceeded to bilateral modified radical mastectomy and bilateral lymph node involvement was found, and later disease progressed with skin involvement outside the EBRT treatment field. Additional 25 treatment of palliative radiotherapy was utilized with another 5000cGy, followed by 2 months of chemotherapy to provide better palliation and quality of life. Upon completion of therapy, a unique skin metastasis pattern was noticed. Shortly afterward the patient passed away from severe sepsis secondary to multiple wounds infected by drug-resistant Pseudomonas aeruginosa followed by Clostridium difficile colitis. Conclusion This case shows clinical characteristics of Carcinoma en Cuirasse and provides important considerations for more research to be done to highlight the unique pattern of skin metastasis following radiation and the potential use for radiation to treat chemotherapy-resistant skin metastasis from recurrent invasive breast carcinoma. Citation Format: Chung-Tang Liu, Keri Lanier. Carcinoma en Cuirasse Secondary to Locally Advanced Breast Carcinoma: a case report [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-06.
Abstract GS1-05: Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates
Authors: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge
Journal: Cancer Research (2023)

Abstract Background: Late recurrence of breast cancer after 5 years accounts for about 50% of recurrences in hormone receptor (HR)-positive early breast cancer (EBC). TAILORx established non-inferiority of adjuvant endocrine therapy (ET) given for at least 5 years to chemotherapy plus ET (CET) in EBC and a 21-gene recurrence score (RS) of 11-25, although there was some chemotherapy benefit in women Methods: Eligibility criteria included women 18-75 years with HR-positive, HER2-negative, T1b-T2N0 EBC who agreed to have CT assigned or randomized based on the RS assay. The primary endpoint was invasive disease-free survival (iDFS) in the RS 11-25 group. The “primary analysis” refers to the original prespecified analysis for the primary IDFS endpoint (836 IDFS events at full information in the RS 11-25 group) after a median of 7.5 years. The “updated analysis” was performed after a median followup of 11.0 and 10.4 years in the randomized and overall populations, respectively. Results:10,253 eligible women enrolled between 4/7/06-10/6/10.The updated analysis includes substantially more events that the primary analysis, including IDFS events (1819 vs. 1210), distant recurrences (561 vs. 384), locoregional +/- distant recurrences (764 vs. 543), and deaths (910 vs. 499). The table provides 5 and 12-year event rates (and standard errors) for all arms, and comparisons of the randomized arms. The primary trial conclusions remain unchanged: ET was non-inferior to CET in the randomized group with a RS 11-25. Although recurrence occurred in &amp;lt; 10% by 12 years for a RS 0-25, late recurrence events beyond 5 years exceeded earlier recurrence. Non-recurrence events occurred in about 13% at 12 years (~1%/year), contributing substantially to the IDFS rates. For women Conclusions: The current updated analysis confirms findings from the original primary analysis that ET is non-inferior to CET in HR-positive, HER2-negative, node-negative EBC and a RS 11-25. As in the original primary analysis, the subgroup of women Citation Format: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson Jr, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge. Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-05.
Abstract MS1-1: Oncogene signal transduction and antiestrogen resistance
Authors: Rachel Schiff
Journal: Cancer Research (2023)

Abstract Background: Recent studies suggest that enhancer reprogramming underlies heterogeneity and disease progression in estrogen receptor-positive (ER+) BC. Cell-type/state specific transcription is governed by high-order assemblies of master transcription factors (TFs) and epigenetically defined regulatory regions including super-enhancers (SEs). We previously showed that aberrant activation of the pioneer TF FOXA1 promotes enhancer and transcriptional reprogramming in endocrine-resistant BC, involving the ER and the AP-1 FRA1 and c-JUN TFs. As SEs maintain a robust cell-type/state specific core transcriptional regulatory circuitry (CRC) in developmental and tumorigenic processes, we sought to identify key additional TFs in SE/FOXA1-driven CRCs in endocrine resistance, which could serve as attractive therapeutic targets. Methods: TF binding motif at the shared SEs (mapped by H3K27ac ChIP-seq) between MCF7-parental (P) cells with ectopic FOXA1 overexpression (OE) and the endogenous FOXA1-amplifed tamoxifen-resistant (TamR) cells was analyzed by HOMER. ER-bound SEs distinguishing TamR vs. P cells were defined by integrating the SEs with our prior ER ChIP-seq data (PMID 28507152). KLF4 motif within these ER-bound SEs was scanned using FIMO and linked to nearby genes by intersection with the previously defined promoter-tethered regions (PTRs) (PMID 24141950). Differential gene expression in MCF7-TamR cells upon KLF4 knockdown (KD) by 3 unique siRNAs was analyzed using limma from edgeR. The biological and clinical significance of the KLF4-dependent genes was analyzed using Gene Ontology and survival modeling with METABRIC and the ER+ metastatic BC cohort ( SABCS19-GS2-02 ). Cell migration was assessed by the wound-healing assay. Citation Format: Rachel Schiff. Oncogene signal transduction and antiestrogen resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr MS1-1.
Abstract GS5-05: ZNF689 deficiency promotes intratumor heterogeneity and resistance to immune checkpoint blockade in triple-negative breast cancer
Authors: Li-Ping Ge, Xi Jin, Gen-Hong Di, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Cancer Research (2023)

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses a significant therapeutic challenge. However, the key determinants and underlying mechanisms of ITH in TNBC remain to be fully elucidated. Methods: We used multi-omics data from our cohort (n = 260) and The Cancer Genome Atlas (n = 134) cohort to comprehensively characterize ITH at the genetic and histologic levels. Transcriptomic differences between high ITH and low ITH tumors were compared to identify the core genes contributing ITH in TNBC. Xenograft models were used to examine the role of key determinants in TNBC ITH. The molecular mechanism was investigated by mass spectrometry, coimmunoprecipitation, pull-down, RNA-seq, long interspersed element-1 (LINE-1) reporter, ATAC-seq, luciferase reporter assays, chromatin immunoprecipitation, flow cytometry and coculture assay. Results: We found that high ITH was associated with poor patient survival and immune checkpoint blockade (ICB) resistance, which were validated in four independent ICB-treated trials. Further analysis indicated zinc finger protein 689 (ZNF689) deficiency as an important determinant of TNBC ITH. Mechanistically, the ZNF689-TRIM28 complex directly bound to the promoter of LINE-1, inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which promoted ITH. ZNF689 deficiency-induced ITH inhibited antigen presentation and CD8+ T cell infiltration, leading to ICB resistance. Pharmacological inhibition of LINE-1 retrotransposition reduced ITH, augmented antitumor immunity, and eventually sensitized ZNF689-deficient tumors to ICB. Consistently, ZNF689 expression positively correlated with favorable prognosis and ICB responsiveness in clinical samples. Conclusions: Our study uncovers a new mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with ICB as a novel treatment strategy in TNBC. Citation Format: Li-Ping Ge, Xi Jin, Gen-Hong Di, Yi-Zhou Jiang, Zhi-Ming Shao. ZNF689 deficiency promotes intratumor heterogeneity and resistance to immune checkpoint blockade in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-05.
Abstract P2-22-02: The role of circular RNAs in triple-negative breast cancer and chemotherapy resistance
Authors: Xiyin Wang, Michael Emch, John Hawse
Journal: Cancer Research (2023)

Abstract Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype representing 15-20% of all breast cancers. TNBC often ends with a poor clinical outcome due to high histological grade and recurrence rates with few treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance, and alternative treatment strategies for the chemoresistant disease remain a major unmet need. circRNAs are newly identified non-coding RNA molecules with covalently closed circular structures. Recently, an increasing number of studies have indicated that circRNAs play crucial roles in regulating tumor development and chemoresistance. However, the role of circRNAs in the process of TNBC chemotherapy resistance is not yet fully clear. Materials and methods: To study the molecular functions of circRNAs in TNBC chemoresistance, identify alternative biomarkers for chemotherapy-resistant disease, and elucidate novel therapeutic targets, doxorubicin-resistant (Doxo-R) and paclitaxel-resistant (Taxol-R) cell lines were generated using TNBC models. Results: Doxo-R and Taxol-R cells exhibited a 3- and 12-fold decrease in sensitivity to their respective chemotherapeutic agents. We identified a large spectrum of gene expression changes that were acquired in Doxo-R and Taxol-R cells. The expression of circRNAs was profiled using circRNA microarrays, and top hits were validated using RT-PCR. We identified 429 and 310 circRNAs that were differentially expressed in Doxo-R and Taxol-R resistant cells respectively compared to the parental chemosensitive cell line (|FC| ≥ 1.5; p value &amp;lt; 0.05). Of these, 66 were commonly differentially expressed between the two chemotherapy resistant models. Conclusions: These results revealed that Doxo-R and Taxol-R TNBC cell lines were successfully established and serve as good models for studying the mechanisms of chemotherapy resistance and the regulatory roles of circRNAs in the development of chemoresistance in TNBC. Increasing knowledge of the important functions of circRNAs underlying drug resistance will provide new opportunities for developing efficacious therapeutic strategies and prognostic/predictive biomarkers for TNBC. Citation Format: Xiyin Wang, Michael Emch, John Hawse. The role of circular RNAs in triple-negative breast cancer and chemotherapy resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-22-02.
Abstract P2-26-03: TRAF3 as a regulator of breast cancer aggressiveness
Authors: Anastasios Papanastasiou, Chaido Sirinian, Maria Theakou, Stavros Peroukidis, Dimitrios Chaniotis, Haralabos Kalofonos, Angelos Koutras
Journal: Cancer Research (2023)

Abstract TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway through the interaction with other TRAF molecules and the downregulation of NIK (MAP3K14) kinase. While NF-κB has a well-established role in breast cancer development and progression, TRAF3 which acts as a ubiquitin-ligase in the NF-κB cascade has never been studied in mammary carcinomas. Here by employing breast cancer cell lines in invasion and colony formation assays, we show that TRAF3 forced expression inhibits aggressive traits of breast cancer cells. In addition, immunohistochemistry (IHC) for TRAF3 protein in breast cancer FFPE samples and analysis of TRAF3 gene expression from publicly available data sets, indicates that TRAF3 mRNA and protein expression in breast cancer tissue correlates with Recurrence Free Survival (RFS), Overall Survival (OS) and other clinicopathological parameters such as Histological Grade and proliferation index (ki-67). To our knowledge this is the first report on TRAF3 protein in breast cancer providing preliminary evidence for an inhibitory role of this protein in breast cancer development and progression. Citation Format: Anastasios Papanastasiou, Chaido Sirinian, Maria Theakou, Stavros Peroukidis, Dimitrios Chaniotis, Haralabos Kalofonos, Angelos Koutras. TRAF3 as a regulator of breast cancer aggressiveness [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-03.
Abstract P1-13-11: YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer
Authors: Natasha Ingles, Katrina Piemonte, Salendra Singh, Kristen Weber-Bonk, Ruth Keri
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Due to the lack of receptor expression, there are limited targeted therapies available for TNBC. As a result, TNBC patients are primarily treated with chemotherapies such as taxanes. Although TNBCs initially regress in response to taxane treatment, resistance is common. One mechanism of taxol unresponsiveness/resistance is an increase in chromosomal instability (CIN). Increased CIN can confer survival advantages to cancer cells and increase their aggressiveness. However, CIN levels can be leveraged using drugs that inhibit proteins important for chromosomal stability. Combining CIN-inducing drugs, such as taxanes, can improve treatment efficacy or re-sensitize tumor cells to certain drugs by shifting cells towards a state of maladaptive CIN that is incompatible with cell viability. We have found that the non-receptor SRC family kinase YES1 is crucial for chromosomal stability. YES1 is important for cell division, motility, adhesion, and survival in both normal and TNBC cells. Since taxol and YES1 silencing independently increase chromosomal instability, I hypothesized that combining a YES1 inhibitor (YES1i) with taxanes would shift cells toward an irreversible state of maladaptive CIN, decreasing their survival. I found that YES1 mRNA and protein are upregulated in taxane-resistant cells and that YES1 protein expression correlates with the paclitaxel IC50 in a panel of TNBC cell lines, suggesting that YES1 may drive taxane resistance. Furthermore, I found that a selective YES1 inhibitor (CH6953755) synergizes with paclitaxel and improves taxane response in both in vitro and in vivo TNBC models. In addition, the combination of YES1i and paclitaxel treatment increases phenotypes associated with chromosomal instability more than either drug alone. These data suggest that YES1 inhibition in combination with taxanes represents an innovative and novel drug treatment regimen that improves TNBC patient outcomes. Citation Format: Natasha Ingles, Katrina Piemonte, Salendra Singh, Kristen Weber-Bonk, Ruth Keri. YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-11.
Abstract OT1-03-01: XMT-1660: A Phase 1b trial of a B7-H4 targeted Antibody Drug Conjugate (ADC) in Breast, Endometrial, and Ovarian Cancers
Authors: Erika Hamilton, Arvind Chaudhry, Alexander I. Spira, Sylvia Adams, Nour Abuhadra, Antonio Giordano, Ritesh Parajuli, Hyo S. Han, Amy Weise, Aubri Marchesani, Kate Josephs, Chu Ri Shin, Kevin Kalinsky
Journal: Cancer Research (2023)

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. B7-H4 is a poor prognostic factor and is overexpressed in several cancers including endometrial, ovarian, and breast. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-targeted Dolasynthen antibody drug conjugate with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996 Citation Format: Erika Hamilton, Arvind Chaudhry, Alexander I. Spira, Sylvia Adams, Nour Abuhadra, Antonio Giordano, Ritesh Parajuli, Hyo S. Han, Amy Weise, Aubri Marchesani, Kate Josephs, Chu Ri Shin, Kevin Kalinsky. XMT-1660: A Phase 1b trial of a B7-H4 targeted Antibody Drug Conjugate (ADC) in Breast, Endometrial, and Ovarian Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-01.
Abstract P2-14-22: Evaluation of male breast cancer and the application of sentinel lymph node biopsy: A multi-center retrospective study
Authors: Qingyao Shang, Ya Wei, Guangdong Qiao, Jingruo Li, Xin Wang
Journal: Cancer Research (2023)

Abstract Objective:Sentinel lymph node biopsy (SLNB) is currently used as a routine treatment for breast cancer patients. Many clinical studies, such as the NSABP B-32, have demonstrated that SLNB can safely replace axillary lymph node dissection (ALND) for patients with clinically node-negative breast cancer. However, it may not be applicable for male breast cancer (MBC) patients because they have notably different clinicopathological features from those occurring in females. There is a lack of evidence of SLNB application and safe exemption from ALND in MBC patients. This study aimed to evaluate the application of SLNB to provide information for the standardized treatment of MBC patients. Methods:The MBC patient records from four institutions ranging from January 2001 to November 2020 were retrospectively reviewed. Patients undergoing surgery as a primary treatment were included. Patients with stage IV and non-primary breast cancer were excluded. Patients were followed up postoperatively for survival analysis. The primary outcome was disease-free survival (DFS), and the secondary outcome was overall survival (OS). Results:There were 220 MBC patients with a median age of 60 (range 24-88) years and an average tumor size of 2.3 cm (range 0.5 cm - 6.5 cm). MBC patients were characterized by old age, advanced stage, and higher pathological grade. The median follow-up time was 5.0 (range, 1.0-17.3) years. Survival analysis showed the 5-year DFS and OS were 73.5% and 83.3%, respectively. 66 patients (30%) underwent SLNB and 39% of them showed positive results. 157 patients (71%) underwent ALND, while only half of them had positive nodes, causing unnecessary complications. For 92 patients at clinical early-stage (stage I or IIA), 28 patients only had SLNB as axillary treatment, 26 patients only had ALND and 38 patients underwent SLNB and ALND. From Kaplan-Meier survival analysis, we found that the SLNB showed a non-inferiority to the ALND treatment in DFS (p=0.18) and OS (p=0.055). Conclusion:MBC patients are older at the time of diagnosis and present a higher pathological grade. There are certain obstacles to the broad application of SLNB due to the lower proportion of clinically-negative lymph node patients. However, it is undeniable that SLNB can safely and effectively exempt MBC patients at early-stage with clinically-negative nodes from ALND to reduce subsequent complications. It’s still an ideal criterion for the axillary staging of MBC patients. Clinicopathologic characteristics of MBC patients Citation Format: Qingyao Shang, Ya Wei, Guangdong Qiao, Jingruo Li, Xin Wang. Evaluation of male breast cancer and the application of sentinel lymph node biopsy: A multi-center retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-22.